This application is a resubmission of a new R21 from NIMH. The introduction of antipsychotic drugs for the treatment of schizophrenia has revolutionized the management of this disorder. Nonetheless, these drugs suffer from poor overall efficacy across symptom classes and devastating side effects. The primary mechanism for all drugs used in treating schizophrenia is based on Dr receptor blockade. However, there is little evidence for pathology within the dopamine system itself; instead, the belief is that the dopamine system is being dysregulated by upstream structures. One synapse that has garnered attention is the parvalbumin GABAergic synapse. Indeed, parvalbumin loss is among the most robust findings in the schizophrenia brain. Using an animal model based on developmental disruption, we found that a loss of parvalbumin in the ventral hippocampus corresponds to hyperactivity in this structure, which indirectly causes the dopaminergic neurons to be hyper-responsive to stimuli. This model is consistent with numerous imaging studies in the schizophrenia patient brain. As a consequence, a number of drugs including the mGluR2/3 agonist by Lilly, the PDE10 inhibitor by Pfizer have been developed that target this circuit have been tested for efficacy. However, despite promising preclinical evidence, all have failed to translate to the clinic, leading a number of pharmaceutical companies to cease drug discovery in this arena. However, unlike the preclinical experiments, these drugs were tested in human schizophrenia patients that had been exposed to decades of antipsychotic drug treatment, and then withdrawn for only one week before testing the novel target agent. It has been long known that repeated D2 receptor blockade leads to dopamine supersensitivity, and in fact antipsychotic drug withdrawal supersensitivity psychosis has been reported in the clinic. We posit that prior D2 antagonist antipsychotic drug treatment will interfere with the ability of novel compounds to show clinical efficacy via induction of D2 supersensitivity. Our results show that a drug that specifically targets GABAergic synapses in the hippocampus, a GABA A alpha 5 positive allosteric modulator, has potent and specific actions in the MAM developmental disruption model of schizophrenia. However, following a brief course of antipsychotic drug treatment and withdrawal, this drug is no longer effective in normalizing the dopamine system. We propose to test whether this also occurs with other novel target agents using this MAM model [and the mechanism underlying this change.] Furthermore, we will test whether the dopamine partial agonist drug aripiprazole, an effective antipsychotic drug that may not induce supersensitivity, can be used as a transitional agent in testing novel target drugs in the absence of supersensitivity. We believe that such experiments are critical in understanding why drugs have failed to translate from preclinical studies into clinical investigations, and to chart a course whereby future studies can be conducted without such endogenous confounds in their design.